Marijuana (Cannabis sativa) is the most widely used illegal drug of abuse in the U.S. The active ingredients of this drug, which include delta9-tetrahydrocannabinol (THC), are collectively known as cannabinoids (CBs). Several scientific advances in the last decade, including the cloning of specific CB receptors, and the identification of endogenous agonists for these receptors, provide an opportunity to evaluate the function of the CB system in regulating neuronal activity both acutely, and during long-term CB exposure. One of the primary consequences of CB receptor activation is the presynaptic inhibition of the major inhibitory (GABA) and excitatory (glutamate) amino acid neurotransmitters in the mammalian brain. Our own published and preliminary data examining CB actions in brain slices suggest that CB receptor activation causes a pronounced inhibition of GABAergic synaptic transmission in both the hippocampus and the nucleus accumbens. These effects in the hippocampus may be at least partly responsible for the well-known disruption of short-term memory caused by marijuana consumption, whereas the direct effects observed in the nucleus accumbens may be responsible for at least some of the rewarding or pleasurable properties of this drug that are presumed to sustain its use in humans. The goal of the experiments described in thus proposal is to understand the neurobiological substrates upon which CB drugs act to alter CNS function, with particular emphasis on the modulation of synaptic transmission: in these two relevant brain: areas. To this end, these studies will identify the molecular mechanisms through which CBs alter synaptic transmission in these specific neuronal circuits, will determine what role endogenously occurring CBs play in regulating neuronal activity, and will establish whether physiological correlates of CB tolerance and dependence can be identified so that we may further understand the neurobiological consequences of long-term marijuana exposure. These experiments will utilize electrophysiological techniques, combined with differential interference microscopy to identify specific neurons in living brain slices. We will then conduct studies with several recently developed pharmacological agents that disrupt endogenous CB catabolism and re-uptake by neurons. In addition, single-cell anatomical techniques will be incorporated into these studies so that the neurons involved in these interactions can be conclusively identified based upon morphological and histochemical features. These studies will significantly increase our understanding of the neurobiology of CBs, and will provide information that should prove relevant to understanding the cellular consequences of long-term CB exposure in humans.